Irritable Bowel Syndrome (IBS) is a common functional gastrointestinal (GI) disorder characterized by abdominal pain and alterations in bowel pattern. IBS disproportionately affects women; 10-15% of women are affected. IBS is challenging to patients and health care providers in that the mechanism(s) accounting for symptoms are not well understood and treatment options are not consistently effective. The disorder is associated with variable levels of distress ranging from episodic mild to severe and at times disruptive to work and school. In terms of annual health care dollars, IBS is ranked second behind GERD. The focus of our work to date has been to understand those biobehavioral, gender, and psychological distress factors linked to symptom type and severity. Intriguing results support the hypothesis that psycho-logical, physiological and target gene polymorphisms differences exist in IBS subgroups. Psychological distress, the autonomic nervous system and serotonin transporter protein polymorphisms may serve as biomarkers of symptom type and severity in women with IBS. Validation of these biomarkers in patients with IBS could lead to development of targeted, novel therapies for subgroups with IBS. In this competitive renewal (R01NR 0194) application we propose to test the primary hypothesis that the divergence in vagal tone is associated with visceral sensitivity. We will also assess the physiologic links between vagal tone and other indicators of central mechanisms (arousal [startle reflex], and descending noxious inhibitory control). Results will allow us to examine biomarkers within a common heterogeneous condition. Specific aims: 1) Test the relationship between vagal tone and central arousal (startle reflex and diffuse noxious inhibitory control [DNIC]) in women with moderate to severe IBS; 2) compare indicators of central arousal mechanisms (startle reflex, DNIC) and upper GI visceral hypersensitivity (water loading), in three groups: moderate to severe diarrhea-predominant IBS versus women with moderate to severe constipation-predominant IBS versus control women; 3) test the relationship between vagal tone and rectal hypersensitivity in a subset of the women; 4) explore the relationships of startle reactivity, DNIC , and upper GI visceral hypersensitivity with genotype (SERT, 12-ADR, COMT, BNDF), abdominal pain reports, childhood abuse history, health related quality of life, current stress, and current and history of psychological distress. Results will increase our understanding of the underlying mechanisms accounting for chronic symptom reports as well as to examine biomarkers within a common heterogeneous condition, IBS.